ESRRA

Chr 11

estrogen related receptor alpha

Also known as: ERR1, ERRa, ERRalpha, ESRL1, NR3B1

NCBI Gene: 2101 ENSG00000173153 UniProt: P11474

This nuclear receptor functions as a transcription factor that regulates genes involved in cellular energy production and mitochondrial biogenesis, often working with PGC-1 family cofactors. Mutations cause autosomal recessive developmental and epileptic encephalopathy with onset in early infancy, characterized by severe intellectual disability, seizures, and metabolic dysfunction. The gene shows significant constraint against loss-of-function variants (LOEUF 0.49), indicating that complete loss of function is likely detrimental.

ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a nuclear receptor that is most closely related to the estrogen receptor. This protein acts as a site-specific transcription factor and interacts with members of the PGC-1 family of transcription cofactors to regulate the expression of most genes involved in cellular energy production as well as in the process of mitochondrial biogenesis. A processed pseudogene of ESRRA is located on chromosome 13q12.1. [provided by RefSeq, Jun 2019]

ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.49

LOEUF

—

Mechanism

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.49LOEUF

pLI 0.597

Z-score 2.99

OE 0.19 (0.09–0.49)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.08Z-score

OE missense 0.63 (0.56–0.72)

161 obs / 254.1 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.19 (0.09–0.49)

0≤0.351.4

Missense OE?0.63 (0.56–0.72)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 3 / 15.8Missense obs/exp: 161 / 254.1Syn Z: 0.33

Background carrier burden — how many people carry a rare variant somewhere in ESRRA?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 140

454 rare PASS variants

Rare truncating (LoF)

1 in 1,900

35 rare PASS variants

Rare synonymous (reference)

1 in 100

263 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ESRRA. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 160	1 in 2,300
South Asian	~43k	1 in 77	1 in 2,300
Remaining (unassigned)	~30k	1 in 150	1 in 900
European (Finnish)	~27k	1 in 180	≈ 1 in 8,700
Admixed American	~22k	1 in 130	1 in 490
African / African American	~21k	1 in 100	1 in 1,300
East Asian	~20k	1 in 200	none seen
Ashkenazi Jewish	~13k	1 in 530	1 in 580
Middle Eastern	~2,881	1 in 250	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 6 coding exons well covered in gnomAD exomes and genomes.? see exons ↓